1. Field of the Invention
2. Description of the Related Art
Targeted drug delivery is a powerful strategy in the treatment and diagnosis of various human diseases, such as cancer, bacterial and viral infections and any disease expressing specific and targetable receptors, antigens or other markers. Targeted drug delivery has gained momentum during the past several years based on the specific delivery therapeutic molecules to malignant tissues comprising the disease state, such as the delivery of oncolytic agent to the neoplastic tissue. The ability to specifically target therapeutic molecules to specific cells of interest has advanced considerably during the past several years with the development of monoclonal antibodies and of synthetic small molecule peptides (SSMPs) capable of binding to tumor cell surface receptors. A number of drug, toxin, and radioisotope conjugates of tumor-recognizing molecules have been developed with some currently in clinical use.
Allergic reactions against large-molecule antibodies in humans due to the immunoreactivity of these proteins have hampered the desired development of antibody-drug conjugates for targeted delivery and much attention has been focused on the SSMPs which usually show no immunoreactivity due to smaller molecular sizes. With the exception of radiolabeled peptides, SSMPs have not been fully utilized as targeting drug delivery systems. Recently, the use of SSMPs in a targeted drug delivery systems with a paclitaxel-bombesin conjugate as a model compound was demonstrated (Safavy, U.S. Pat. No. 6,191,290, 2001; Safavy et al., J Med Chem, 1999, 42, 4919-4924). This and similar molecules will be referred to as single drug, single ligand (SDSL) conjugates. While effective at specifically delivering the therapeutic molecule to the target cell of interest, these SDSL conjugates have several limitations. First, the biological half-life of these SDSL conjugates is quite short, with the conjugates undergoing rapid clearance from the circulation (usually on the order of 1 to 5 minutes). As a result, only a fraction of the SDSL conjugates are taken up by the target cells, which results in a low therapeutic efficiency. Secondly, the ability to adapt SDSL conjugates to various disease states or to deliver different therapeutic molecules is limited. It would be beneficial if a conjugate were provided that is designed to deliver different therapeutic molecules to the target cells with a minimum of experimental manipulation.
Therefore, it would be advantageous to provide a pharmaceutical compound for use in a single-step drug delivery method that is capable of specifically delivering to target cells (via a targeting conjugate) multiple copies of the same or different therapeutic agent(s). This approach may result in higher therapeutic indices which may bring about a more significant response from the target cells. The present disclosure provides such a strategy and provides a method for the synthesis of a model conjugate as proof-of principle. This model conjugate was used in a tumor cell proliferation assay to demonstrate the drug-enhancing potential of this approach.